TY - JOUR T1 - In Vitro Metabolism, Permeability, and Efflux of Bazedoxifene in Humans JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1471 LP - 1479 DO - 10.1124/dmd.109.030999 VL - 38 IS - 9 AU - Li Shen AU - Syed Ahmad AU - SeongHee Park AU - William DeMaio AU - Aram Oganesian AU - Theresa Hultin AU - JoAnn Scatina AU - Peter Bungay AU - Appavu Chandrasekaran Y1 - 2010/09/01 UR - http://dmd.aspetjournals.org/content/38/9/1471.abstract N2 - Bazedoxifene (BZA) acetate, a novel estrogen receptor modulator being developed for the prevention and treatment of postmenopausal osteoporosis, undergoes extensive metabolism in women after oral administration. In this study, the in vitro metabolism of [14C]BZA was determined in human hepatocytes and hepatic and intestinal microsomes, and the UDP glucuronosyltransferase (UGT) isozymes involved in the glucuronidation of BZA were identified. In addition, BZA was evaluated for its potential as a substrate of P-glycoprotein (P-gp) transporter in Caco-2 cell monolayers. BZA was metabolized to two monoglucuronides, BZA-4′-glucuronide and BZA-5-glucuronide, in hepatocytes and in liver and intestinal microsomes including jejunum, duodenum, and ileum. Both BZA-4′-glucuronide and BZA-5-glucuronide were major metabolites in the intestinal microsomes, whereas BZA-4′-glucuronide was the predominant metabolite in liver microsomes and hepatocytes. The kinetic parameters of BZA-4′-glucuronide formation were determined in liver, duodenum, and jejunum microsomes and with UGT1A1, 1A8, and 1A10, the most active UGT isoforms involved in the glucuronidation of BZA, whereas those of BZA-5-glucuronide were determined with all the enzyme systems except in liver microsomes and in UGT1A1 because the formation of the BZA-5-glucuronide was too low. Km values in liver, duodenum, and jejunum microsomes and UGT1A1, 1A8, and 1A10, were similar and ranged from 5.1 to 33.1 μM for BZA-4′-glucuronide formation and from 2.5 to 11.1 μM for BZA-5-glucuronide formation. Vmax values ranged from 0.8 to 2.9 nmol/(min · mg) protein for BZA-4′-glucuronide and from 0.1 to 1.2 nmol/(min · mg) protein for BZA-5-glucuronide. In Caco-2 cells, BZA appeared to be a P-gp substrate. ER -